linoleic-acid and adrenic-acid

Polyunsaturated fatty acids (PUFAs) are closely related to various physiological conditions. In several age-related diseases including Alzheimer's disease (AD) altered PUFAs metabolism has been reported. However, the mechanism behind PUFAs impairment and AD developpement remains unclear. In humans, PUFAs biosynthesis requires delta-5 desaturase (D5D), delta-6 desaturase (D6D) and elongase 2 activities; which are encoded by fatty acid desaturase 1 (FADS1), fatty acid desaturase 2 (FADS2), and elongation of very-long-chain fatty acids-like 2 (ELOVL2) genes, respectively. In the present work, we aim to assess whether genetic variants in FADS1, FADS2 and ELOVL2 genes influence plasma and erythrocyte PUFA composition and AD risk. A case-control study was carried out in 113 AD patients and 161 healthy controls.Rs174556, rs174617, and rs3756963 of FADS1, FADS2, and ELOVL2 genes, respectively were genotyped using PCR-RFLP. PUFA levels were quantified using Gas Chromatography. Genotype distributions of rs174556 (FADS1) and rs3756963 (ELOVL2) were different between case and control groups. The genotype TT of rs174556 and rs3756963 single nucleotide polymorphism (SNP) increases significantly the risk of AD in our population. PUFA analysis showed higher plasma and erythrocyte arachidonic acid (AA) level in patients with AD, whereas only plasma docosahexaenoic acid (DHA) was significantly decreased in AD patients. The indexes AA/Dihomo-gamma-linolenic acid (DGLA) and C24:4n-6/Adrenic acid (AdA) were both higher in the AD group. Interestingly, patients with TT genotype of rs174556 presented higher AA level and AA/DGLA index in both plasma and erythrocyte. In addition, higher AA and AA/DGLA index were observed in erythrocyte of TT genotype ofrs3756963 carrier's patients. Along with, positive correlation between AA/DGLA index, age or Gamma-linolenic acid (GLA)/ Linoleic acid (LA) index was seen in erythrocyte and /or plasma of AD patients. After adjustment for confounding factors, the genotype TT of rs174556, erythrocyte AA and AA/DGLA index were found to be predictive risk factors for AD while plasma DHA was found associated with lower AD risk. Both rs174556 and rs3756963 influence AD risk in the Tunisian population and they are likely associated with high AA level. The combination of the two variants increases further the susceptibility to AD. We suggest that FADS1 and ELOVL2 variants could likely regulate the efficiency of AA biosynthesis which could be at the origin

Topics: 8,11,14-Eicosatrienoic Acid; Alleles; Alzheimer Disease; Arachidonic Acid; Case-Control Studies; Chromatography, Gas; Delta-5 Fatty Acid Desaturase; Docosahexaenoic Acids; Erythrocytes; Fatty Acid Desaturases; Fatty Acid Elongases; Fatty Acids, Unsaturated; gamma-Linolenic Acid; Genotype; Humans; Linoleic Acid; Polymorphism, Single Nucleotide; Regression Analysis; Risk Factors; Tunisia

Apolipoprotein D (apoD), a member of the lipocalin superfamily of lipid-binding proteins, exhibits abundant expression within the CNS of many species, including humans; however, its physiological role remains unclear. Treatment with atypical antipsychotic drugs, especially clozapine, results in elevation of apoD expression levels in rodent brain and in human plasma samples. In order to further explore the role of apoD in mechanisms of clozapine function, we have measured a panel of membrane fatty acids and membrane lipids in brain from drug-treated apoD knock-out mice. Mice received clozapine (10 mg/kg/day) in their drinking water for 28 days and forebrain samples were analyzed using high performance liquid chromatography and capillary gas chromatography. We identified significant differences in the levels of membrane fatty acids in response to clozapine treatment specifically in the brains of apoD knock-out mice, but not wild-type (wt) mice. The most striking observations were decreases in the levels of fatty acids related to metabolism of arachidonic acid (AA), which is a known binding partner for apoD. These include the precursor to arachidonic acid, linoleic acid (LA; 18:2n6c), arachidonic acid itself (20:4n6) and the elongation product of arachidonic acid, adrenic acid (22:4n6). We further report increases in LA, eicosadienoic acid and docosahexaenoic acid in apoD knock-out compared to wild-type mice. These findings implicate an important apoD/AA interaction, which may be necessary for clozapine function.

Topics: Animals; Antipsychotic Agents; Apolipoproteins D; Arachidonic Acid; Chromatography, Gas; Chromatography, High Pressure Liquid; Clozapine; Erucic Acids; Fatty Acids; Fatty Acids, Unsaturated; Linoleic Acid; Membrane Lipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Prosencephalon

Starting three weeks before mating, 12 groups of female rats were fed different amounts of linoleic acid (18:2n-6). Their male pups were killed when 21-days-old. Varying the dietary 18:2n-6 content between 150 and 6200 mg/100 g food intake had the following results. Linoleic acid levels remained very low in brain, myelin, synaptosomes, and retina. In contrast, 18:2n-6 levels increased in sciatic nerve. In heart, linoleic acid levels were high, but were not related to dietary linoleic acid intake. Levels of 18:2n-6 were significantly increased in liver, lung, kidney, and testicle and were even higher in muscle and adipose tissue. On the other hand, in heart a constant amount of 18:2n-6 was found at a low level of dietary 18:2n-6. Constant levels of arachidonic acid (20:4n-6) were reached at 150 mg/100 g diet in all nerve structures, and at 300 mg/100 g diet in testicle and muscle, at 800 mg/100 g diet in kidney, and at 1200 mg/100 g diet in liver, lung, and heart. Constant adrenic acid (22:4n-6) levels were obtained at 150, 900, and 1200 mg/100 g diet in myelin, sciatic nerve, and brain, respectively. Minimal levels were difficult to determine. In all fractions examined accumulation of docosapentaenoic acid (22:5n-6) was the most direct and specific consequence of increasing amounts of dietary 18:2n-6. Tissue eicosapentaenoic acid (20:5n-3) and 22:5n-3 levels were relatively independent of dietary 18:2n-6 intake, except in lung, liver, and kidney. In several organs (muscle, lung, kidney, liver, heart) as well as in myelin, very low levels of dietary linoleic acid led to an increase in 20:5n-3.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adipose Tissue; Animals; Arachidonic Acid; Arachidonic Acids; Brain; Dietary Fats; Eicosapentaenoic Acid; Erucic Acids; Fatty Acids, Unsaturated; Female; Kidney; Linoleic Acid; Linoleic Acids; Lung; Male; Muscles; Myocardium; Nerve Tissue; Nutritional Requirements; Rats; Rats, Inbred Strains; Testis

In a previous paper we reported that arachidonic acid (20:4(n-6] strongly enhances the endothelial cell synthesis of prostaglandin I3 (PGI3) from eicosapentaenoic acid (20:5(n-3], in stimulating the cyclooxygenase rather than the prostacyclin synthase (Bordet et al. (1986) Biochem. Biophys. Res. Commun. 135, 403-410). In the present study, endothelial cell monolayers were co-incubated with exogenous 20:5(n-3) or docosatetraenoic acid (22:4(n-6], and n-6 lipoxygenase products of 20:4(n-6) or linoleic acid (18:2(n-6], namely 15-HPETE and 13-HPOD, respectively. Prostaglandins or dihomoprostaglandins were then measured by gas chromatography-mass spectrometry. Both hydroperoxides, up to 20 microM, stimulated the cyclooxygenation of 20:5(n-3) and 22:4(n-6), in particular the formation of PGI3 and dihomo-PGI2, respectively. Higher concentrations inhibited prostacyclin synthetase. In contrast, the reduced products of hydroperoxides, 15-HETE and 13-HOD, failed to stimulate these cyclooxygenations, 13-HPOD appeared more potent than 15-HPETE and the cyclooxygenation of 22:4(n-6) seemed to require higher amounts of hydroperoxides to be efficiently metabolized than 20:5(n-3). These data suggest that prostacyclin potential of endothelium might be enhanced by raising the peroxide tone.

Topics: Arachidonic Acid; Arachidonic Acids; Cells, Cultured; Endothelium, Vascular; Epoprostenol; Erucic Acids; Fatty Acids, Unsaturated; Gas Chromatography-Mass Spectrometry; Humans; Kinetics; Leukotrienes; Linoleic Acid; Linoleic Acids; Lipid Peroxides; Lipoxygenase; Mass Spectrometry; Prostaglandins F; Umbilical Veins